Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for a variety of hematologic and immunologic diseases. However, graft-versus-host disease (GVHD) remains the major complication that causes significant morbidity and mortality despite the currently practiced immunosuppressive therapies. GVHD is known to be caused by donor-derived T cells that recognize allogeneic antigens expressed on host cells and subsequently damage host normal tissues. In addition to TCR signaling stimulated by MHC- antigen complex, co-stimulatory pathways are involved in T cell activation and function. The co-stimulatory molecule CD27 is a TNF receptor family member expressed on T cells and its ligand, CD70, is known to be expressed on activated antigen-presenting cells (APC) as well as T cells. Previous studies using mainly viral infection models have largely described this pathway as ?stimulatory? and required for optimal T cell responses, while its role in allo-HCT is previously unknown. In this project, we have used established murine models to study the roles of CD27/CD70 in GVHD. Our results reveal a novel inhibitory role played by this pathway as specified in 2 aspects: 1) allo-HCT shows that both CD27-/- and CD70-/- donor T cells caused more severe GVHD than WT donor T cells, suggesting that CD27/CD70 signaling in donor T cells inhibits allogeneic T cell response; 2) when used as hosts for allo-HCT, both CD27-/- and CD70-/- mice exhibited more severe GVHD compared to WT hosts, suggesting that CD27/CD70 signaling in the host inhibits allogeneic T cell response. Initial mechanistic analyses suggest that this pathway inhibits GVHD by limiting donor T cell expansion and reducing pro-inflammatory cytokines in a donor regulatory T cell-independent fashion. Based on these results, our central hypothesis is that CD27/CD70 signaling plays a novel role suppressing GVHD by inhibiting allogeneic inflammatory T cell response. We propose three aims to systematically pursue donor T cell-derived mechanisms, host-derived mechanisms and clinical relevance of this pathway in the context of GVHD. Understanding such mechanisms will be critical for developing innovative strategies that can control GVHD and improve quality of life for allo-HCT patients.